PROJECT SUMMARY Sickle cell disease (SCD) is a hereditary blood disorder, which affects more than 70,000 patients in the US. It can lead to a wide range of serious, sometimes life-threatening, conditions including: chronic hemolytic anemia, chronic pain and acute painful crisis, stroke, and cumulative damage to tissues and organs. Median mortality in the US from SCD is estimated to be 39 years. The only existing therapy approved for SCD is the anti-cancer agent hydroxyurea (HU). HU is not effective for many patients and has a wide variety of serious side-effects. AesRx is developing Aes-103 as an orally bioavailable, chronic therapy for SCD. It is well established that only deoxygenated sickle hemoglobin polymerizes and causes the rigid sickle-shaped red blood cells (RBCs) that give the disease its name. The active ingredient in Aes-103 is 5-hydroxymethyl-2-furfural (5-HMF), a naturally occurring small molecule. Through direct binding to hemoglobin, Aes-103 prevents polymerization and ultimately the formation of rigid, sickled RBCs. Moreover, recent in vitro research conducted at the NIH indicates Aes-103 also stabilizes sickle red blood cells and protects them from shear stress which is an important feature of SCD. To AesRx's knowledge, Aes-103 is the only direct anti-sickling agent in or near clinical trials. This award supports the conduct of a Phase 2 clinical trial that will evaluate (i) Aes-103's safety profile, (ii) its pharmacokinetics (PK), (iii) its pharmacodynamics (PD) and (iv) its efficacy in SCD patients. It is designed to provide a clear path for Aes-103 into Phase 3 clinical studies and ultimately approval by the FDA for its use in patients. AesRx's study will be a sequential cohort, adaptive design, placebo- controlled, randomized, double-blind study of two dose levels of Aes-103 in up to 50 SCD subjects. Adult subjects will receive Aes-103 up to four times daily at two sequential dose levels for up to 28 days and will be compared with subjects receiving placebo. Safety endpoints assessed will be the frequency and severity of adverse events and SCD-related symptoms. PK endpoints include maximum concentration (Cmax) and half-life (t1/2) of Aes-103. PD endpoints will include the percentage of hemoglobin bound to Aes-103, the percentage of sickled RBCs under normal and hypoxic conditions. Efficacy endpoints will examine changes in hemoglobin levels, reduction in chronic/recurrent pain and increase in exercise tolerance in the treated patients compared to placebo. The impact to public health as a result of this study is potentially significant. Complications from poor management of SCD can cause significant long-term morbidity, early mortality and result in high medical and economic costs. With this award, AesRx will provide critical data enabling pivotal trials of potentially the first ever direct anti-sickling drug for SCD.